Amphiregulin Promotes Proliferation and Migration of the Damaged Endothelial Cells in Kawasaki Disease Cell Models

Objectives: Amphiregulin (Areg), a member of the epidermal growth factor family, plays a critical role in tissue repair, inflammation, and immunity. Macrophages are an important source of Areg and are also among the key immune cells activated in Kawasaki disease (KD). Despite this, the role of Areg in KD has not been studied. Therefore, this study aims to investigate the expression of Areg in a KD model and to elucidate its effects on injured endothelial cells using a KD cell model.

Methods: The serum of LCWE-induced KD mouse model was measured by ELISA. RAW264.7 cells were stimulated with LCWE, and the supernatant was collected. Then, MCAECs were treated with LCWE-induced RAW264.7 cells conditioned medium (RAW-CM) to simulate inflammatory damage in KD endothelial cells.

Results: Our study showed that the serum level of Areg increased in LCWE-induced mouse model. In vitro, LCWE increased the expression and secretion of Areg in RAW264.7 macrophages, an effect that was inhibited by ADAM-17 blockade. The conditioned medium (CM) from LCWE-stimulated RAW264.7 cells (RAW-CM) enhanced the proliferative capacity of endothelial cells, an effect that was partially inhibited by Areg antibodies. Recombinant Areg promoted the proliferation and migration of damaged endothelial cells, effects that were dependent on the activation of the Akt and ERK signaling pathways.

Conclusion: This study demonstrates that serum Areg level increased in LCWE-induced KD mouse model, and Areg promoted proliferation and migration abilities of injured endothelial cells. Our work suggests that Areg may be one of the reasons for the repair of injured endothelial cells in LCWE model vasculitis.

Kawasaki disease; amphiregulin; coronary artery endothelial cells; inflammation; macrophages.